Hepatocellular carcinoma (HCC) is the fifth most common cancer and a leading cause of cancer related death worldwide (Nakagawa et al., 2014, Cancer Cell. 26: 331-343). The pathogenesis of HCC has been mostly associated with cirrhosis due to chronic infection by hepatitis B virus and hepatitis C virus, as well as due to toxic injury from alcoholism (E I Seag, 2011, N Eng J Med 365: 118-127). While a substantial number of cases cannot be explained by these etiologies, HCC is increasingly diagnosed among obese individuals (Turati et al., 2913, Br J Cancer 108: 222-228). Obesity and obesity-related disorders such as non-alcoholic fatty liver disease (NAFLD), steatohepatitis, insulin resistance and type 2 diabetes exhibit an increased risk for developing HCC (Tilg et al., 2014, Best Pract Res Clin Gastroenterol 28:599-610). For instance, in a large prospective cohort of the Cancer Prevention Study in North American subjects, the relative risk of dying from liver cancer among men with a BMI≥35 kg/m2 was 4.5 fold higher compared to a reference group with normal body weight (Calle et al., 2003, N Engl J Med 348: 1625-1638). Similarly, in a Swedish cohort study of men, the relative risk of HCC in individuals with a BMI≥30 kg/m2 was 3.1 fold higher than in normal weight controls (Samanic et al., 2006, Cancer Causes Control 17: 901-909). Similar findings have been reported from other parts of the world (Wolk et al., 2001, Cancer Causes Cotrol 12: 13-21; Borena et al., 2012, Int J Cancer 131: 193-200; Schlesinger et al., 2013, Int J Cancer 132: 645-657). Obesity increases male HCC risk by 4-8 fold (Calle et al., 2004, Nat Rev Cancer 4: 579-591), and also increases HCC risk in viral hepatitis (Chen et al., 2008, Gastroenterology 135: 111-121). Furthermore, obesity associated tumors appear to be more aggressive, have an increased risk of recurrence, and result in higher mortality (Carmichael, 2006, BJOG 113: 1160-1166; Murphy et al., 2000, Am J Epidemiol 152: 847-854).
Hepatic manifestations of obesity and metabolic syndrome are collectively termed NAFLD, which is commonly associated with insulin resistance and hyperinsulinemia (Marchesini et al., 1999, Am J Epidemiol 152: 847-854). In general, NAFLD is apparently benign, but approximately 20% of all cases present as nonalcoholic steatohepatitis (NASH) featuring hepatocellular injury and inflammation, with a risk of progression to cirrhosis and HCC (Marrero et al., 2002, Hepatology 36: 1349-1354; Ekstedt et al., 2996, Hepatology 7: 234-238; Rafiq et al., 2007, Clin Gastroenterol Hepatol 7: 234-238). The overall public health impact of an association between NAFLD, NASH and HCC remains substantial considering high prevalence of obesity and related metabolic conditions worldwide. Emerging evidence suggest that NAFLD is associated with the development of non-cirrhotic HCC (Guzman et al., 2008, Arch Pathol Lab Med 132: 1761-1766; Paradis et al., 2009, Hepatology 42: 851-859; Ertle et al., 2010, Int J Cancer 128: 2436-2443). For example, in an analysis of the SEER-Medicare database identified a total of 17,895 cases of HCC of which 2,863 cases (16%) were due to biopsy-proven NAFLD without evidence for other etiologies (Rahman et al., 2012, Hepatology 56: 241A). Remarkably, a total of 1,031 cases (36%) of NAFLD-associated HCC were diagnosed in non-cirrhotic livers and 18% of these cases developed in isolated fatty liver without steatohepatitis (Rahman et al., 2012). This suggests that cirrhosis is not necessary for the development of HCC in obesity. Because of the epidemic proportions of obesity, there is an increasing probability that adverse metabolic conditions coexist with chronic liver disease, and obesity-associated abnormalities may enhance the effect of other established risk factors of HCC. Several studies support this notion such as alcoholic liver disease and chronic viral hepatitis associated HCC (Karagozian et al., 2014, Metabolism Clinical and Experimental 63: 607-617).
A number of molecular mechanisms have been linked to obesity and its associated abnormalities that may facilitate the development of HCC, such as adipose tissue inflammation, hepatic lipotoxicity, and insulin resistance (Karagozian et al., 2014). These and other pathological events in obesity have complex interactions while their relative contribution to the development of HCC in various stages of hepatic steatosis progression remains to be determined. Because of the continuous increase in obesity associated hepatic steatosis worldwide, there is an urgent need to better understand the underlying mechanism involved in obesity-linked HCC development. However, one major obstacle for the mechanistic study is the lack of suitable animal models that spontaneously develop obesity associated NAFLD, NASH and HCC in a progressive manner. For example, the majority of the studies investigating the impact of obesity on transgene or carcinogen-induced HCC development or progression have been done using diet-induced obese (DIO) models (Nakagawa et al., 2014; Umemura et al., 2014, Cell Metab 20: 133-144; Duan et al., 2014, BMC Gastroenterol 20: 195; Tajima et al., 2013, Am J Physiol Endocrinol Metab 305: E987-998). A major disadvantage of DIO model is that it is very difficult to discern the effect of diet from overweight/obesity and obesity from insulin resistance, which often coexist. Likewise, mechanisms involved in the development and progression of carcinogen-induced HCC may not apply to obesity-linked HCC in humans that develop progressively due to systemic changes in the body. Thus, suitable preclinical models that incorporate natural history estimates of disease progression are needed for a better understanding of the mechanisms of obesity-linked NASH and HCC. In addition, a suitable animal model is required for appropriate and meaningful intervention and preclinical studies.
Emerging evidence suggests that obesity is a risk factor for different types of cancer, and obesity at the time of cancer diagnosis is associated with poorer survival rates (Renehan et al., 2008, Lancet 371: 569-578; Wolin et al., 2010, Oncologist 5: 556-565). Furthermore, obese patients are at a greater risk of tumor recurrence and metastasis (Makarem et al., 2015, Cancer Causes Control 26: 277-286). The mechanisms underlying these associations are not understood, partly due to the lack of suitable animal models and the difficulties associated with human studies. Several hypotheses have been proposed to explain this association. One of them is centered on adipose tissue as an endocrine organ and obesity as an endocrine disorder with increased circulating levels of insulin, bioavailable IGF-I, estrogen, inflammatory cytokines and leptin (Hernandez et al., 2015, Cancer Med 10:375; Madeddu et al., J Cell Mol Med 18: 2519-2529; Rose et al., 2004, Obes Rev 5: 153-165). There is accumulating evidence suggesting that the metabolic effects of obesity through insulin resistance are risk factors for cancer development (DeCensi et al., 2014, Breast Cancer Res Treat 148: 81-90; Zhao et al., 2014, World J Clin Oncol 5: 248-262). This evidence is primarily derived from epidemiological studies indicating that patients with metabolic syndrome have a higher incidence of cancer (Renehan et al., 2006, Trends Endocrinol Metab 17: 328-336). In patients with insulin resistance, the reduced sensitivity of metabolic tissues to insulin results in elevated blood glucose and insulin levels. Chronic hyperinsulinemia promotes the secretion of IGF-I and reduces the production of IGF binding proteins, which in turn further increases bioavailable IGF-I (Gallagher et al., 2013, Diabetes 62: 3553-3560). Through the IGF-I receptor, IGF-I and/or insulin activate downstream signaling pathways that promote mitogenic and proangiogenic factors and inhibit apoptosis (Renehan et al., 2006; Gallagher et al., 2013). Insulin itself is mitogenic and antiapoptotic (Renehan et al., 2006). These mediators, along with their interacting partners and pathways, form the complex molecular network by which obesity impacts the pathological manifestation of carcinogenesis. However, it is not known how physiological factors like insulin, estrogen, leptin and IGF-I lead to cancer growth.
A number of studies have been done to address the connection between obesity and cancer, using common obese rodent models (Gallgher et al., 2013; Gahete et al., 2014, Carcinogenesis 35: 2467-2473; Hvid et al., 2013, PLoS One 8: 79710). In the majority of the studies, either genetically obese (e.g. ob/ob, db/db) or diet-induced obese rodent models have been used to investigate transgene and carcinogen-induced tumor development (Gahete et al., 2014; Hvid et al., 2013; Nakagawa et al., 2014). To study tumor progression, the major focus has been on allograft studies in mice with either genetic or diet-induced obesity (Hvid et al., 2013; Zhang et al., 2009, Cancer Res 69: 5259-5266). In general, obesity has been demonstrated to shorten tumor latency and to worsen tumor pathology. However, in genetic models with a defect in leptin or the leptin receptor, the impact of obesity is not as straightforward (Cleary, 2013, J Mammary Gland Biol Neoplasia 18: 333-343). Likewise, with diet-induced obese rodent models, it is difficult to discern the effect of diet from being overweight and other confounding factors. Thus, there is a lack of apt translational models to study the relationship between obesity, insulin resistance and cancer. Future studies clearly distinguishing the diet component from body weight and obesity from insulin resistance effects, will be important in continuing to understand the factors associated with the impact of body weight on cancer development and progression.
We have been interested in understanding the role and the regulation of cell compartment specific functions of a pleiotropic protein, prohibitin (PHB, also known as PHB1) (Ande et al., 2009, Biochem Biophys Acta 2009: 1372-1378; Ande et al., 2012, In J Obes (Lond) 36: 1236-1244; Ande et al., 2014, Diabetes 63: 3734-3741). PHB localizes to mitochondria and the plasma membrane where it has a cell compartment specific function (Nijtmans et al., 2002, Cell Mol Life Sci 59: 143-155; Sharma et al., 2004, PNAS 101: 17492-17497). In the mitochondria, PHB functions as a lipid and protein chaperone (Richter et al., 2014, Cell Metab 20: 158-171), whereas in association with the plasma membrane, PHB has a role in membrane receptor signaling (Kim et al., 2013, Science Signaling 6:292; Rajalingam et al., 2005, Nat Cell Biol 8: 837-843). We have reported that the phosphorylation of PHB protein at tyrosine-114 residue has a role in intrinsic down regulation of tyrosine kinase signaling (Ande et al., 2009), and others have confirmed its a role in immune signaling (Kim et al., 2013). Recently, we have discovered that PHB has a role in adipocyte differentiation (Ande et al., 2012).